Na(+)-glucose cotransporter inhibitors as antidiabetic agents. II. Synthesis and structure-activity relationships of 4'-dehydroxyphlorizin derivatives.
A novel series of 4'-dehydroxyphlorizin derivatives was synthesized and the effects of these compounds on urinary glucose excretion were evaluated in rats. There was a strict structural requirement for activity. Introduction of a small substituent or a flat ring at the 3- and/or the 4-position on the A ring was permissible, but any change at the bridge part between the A and B rings or in the sugar moiety resulted in complete loss of activity. The 6'-OH group on the B ring was also necessary, and even small structural modifications of the 6'-OH group reduced the activity considerably. Among the compounds synthesized, the 5-benzofuryl derivative 25 was the most potent and was selected as a new lead for further structure-activity relationship investigations.
Hongu
M
M
Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Tanaka
T
T
Funami
N
N
Saito
K
K
Arakawa
K
K
Matsumoto
M
M
Tsujihara
K
K
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D005947:Glucose / Q000378:metabolism; D005960:Glucosides / Q000097:blood; D006029:Glycosuria / Q000652:urine; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors*; D010695:Phlorhizin / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism; D051269:Sodium-Glucose Transporter 1; D013329:Structure-Activity Relationship
D001786:Blood Glucose; D005960:Glucosides; D007004:Hypoglycemic Agents; D008562:Membrane Glycoproteins; D009004:Monosaccharide Transport Proteins; C495676:Slc5a1 protein, rat; D051269:Sodium-Glucose Transporter 1; D012964:Sodium; D010695:Phlorhizin; D005947:Glucose